The pituitary gland is attached by a stalk to the region in the base of the brain known as the hypothalamus. In particular, follicle stimulating hormone (FSH) and luteinizing hormone (LH), sometimes referred to as gonadotropins or gonadotropic hormones, are released by the pituitary gland. These hormones, in combination, regulate the functioning of the gonads to produce testosterone in the testes and progesterone and estrogen in the ovaries, and they also regulate the production and maturation of gametes. Growth hormone(GH) is also released by the pituitary gland.
The release of a hormone by the anterior lobe of the pituitary gland usually requires a prior release of another class of hormones produced by the hypothalamus. One of the hypothalamic hormones acts as a factor that triggers the release of the gonadotropic hormones, particularly LH, and this hormone is referred to herein as GnRH although it has also been referred to as LH-RH and as LRF. GnRH has been isolated and characterized as a decapeptide having the following structure: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2.
Peptides are compounds which contain two or more amino acids in which the carboxyl group of one acid is linked to the amino group of the other acid. The formula for GnRH, as represented above, is in accordance with conventional representation of peptides where the amino or N-terminus appears to the left and the carboxyl or C-terminus to the right. The position of the amino acid residue is identified by numbering the amino acid residues from left to right. In the case of GnRH, the hydroxyl portion of the carboxyl group of glycine has been replaced with an amino group(NH.sub.2). The abbreviations for the individual amino acid residues above are conventional and are based on the trivial name of the amino acid, e.g. pGlu is pyroglutamic acid, His is histidine, Trp is tryptophan, Ser is serine, Tyr is tyrosine, Gly is glycine, Leu is leucine, Orn is ornithine, Arg is arginine, Lys is lysine, Cys is cysteine, Asn is asparagine, Thr is threonine, Pro is proline, Phe is phenylalanine, Glu is glutamic acid, Asp is aspartic acid and Ala is alanine. Except for glycine, amino acids of the peptides of the invention are of the L-configuration unless noted otherwise.
The substitution of a D-amino acid for Gly in the 6-position of the GnRH decapeptide or nonapeptide provides a GnRH analog having substantially greater binding affinity and thus can be used to produce both agonists and antagonists of higher potency. The substitution of an ethylamide moiety or the like for Gly-NH.sub.2 at the C-terminus produces agonists of higher potency. Other substitutions throughout the GnRH decapeptide are known which produce antagonists having an inhibitory effect on the release of LH and other gonadotropins by the pituitary gland of mammalians. Such a releasing or inhibitory effect is obtained when the GnRH analog is administered to a mammalian intravenously, subcutaneously, intramuscularly, orally, percutaneously, e.g. intranasally, intravaginally, or in delayed or timed-release formulations.
There are reasons for desiring to prevent ovulation in female mammalians, and the administration of GnRH analogs that are antagonistic to the normal function of GnRH or of large doses of agonists of GnRH have been used to suppress or delay ovulation. For this reason, such analogs of GnRH are being investigated for their potential use as a contraceptive or for regulating conception periods. GnRH antagonists may also be used for the treatment of precocious puberty and endometriosis. Such antagonists have also been found useful to regulate the secretion of gonadotropins in male mammals and can be employed to arrest spermatogenesis, e.g. as male contraceptives, and for treatment of prostatic hypertrophy.
It is desired to provide improved peptides which are more potent analogs of GnRH.